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- PDB-9zaw: HMG-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7 -

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Basic information

Entry
Database: PDB / ID: 9zaw
TitleHMG-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
ComponentsHydroxymethylglutaryl-CoA synthase, cytoplasmic
KeywordsTRANSFERASE / cytosolic protein / metabolic inhibitor
Function / homology
Function and homology information


farnesyl diphosphate biosynthetic process, mevalonate pathway / hydroxymethylglutaryl-CoA synthase / hydroxymethylglutaryl-CoA synthase activity / Cholesterol biosynthesis / acetyl-CoA metabolic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / lipid metabolic process / PPARA activates gene expression / protein homodimerization activity ...farnesyl diphosphate biosynthetic process, mevalonate pathway / hydroxymethylglutaryl-CoA synthase / hydroxymethylglutaryl-CoA synthase activity / Cholesterol biosynthesis / acetyl-CoA metabolic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / lipid metabolic process / PPARA activates gene expression / protein homodimerization activity / cytoplasm / cytosol
Similarity search - Function
Hydroxymethylglutaryl-coenzyme A synthase, active site / Hydroxymethylglutaryl-CoA synthase, eukaryotic / Hydroxymethylglutaryl-coenzyme A synthase active site. / Hydroxymethylglutaryl-coenzyme A synthase, N-terminal / Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain / Hydroxymethylglutaryl-coenzyme A synthase N terminal / Hydroxymethylglutaryl-coenzyme A synthase C terminal / Thiolase-like
Similarity search - Domain/homology
: / Hydroxymethylglutaryl-CoA synthase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.29 Å
AuthorsAn, H. / Sun, L. / de la Cruz, M.J. / Sen, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: J Am Chem Soc / Year: 2026
Title: Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer.
Authors: Liang Sun / Sang Ah Yi / Brittany Q Pham / Antoine Mocellin / Sagnik Sen / M Jason de la Cruz / Alban Ordureau / Heeseon An /
Abstract: Comprehensive target validation remains a significant bottleneck in chemical probe development, particularly for covalent inhibitors, where off-target reactivity can lead to toxicity. Using HMG-CoA ...Comprehensive target validation remains a significant bottleneck in chemical probe development, particularly for covalent inhibitors, where off-target reactivity can lead to toxicity. Using HMG-CoA synthase 1 (HMGCS1), an underexplored gatekeeper enzyme in the mevalonate pathway, we demonstrate how integrating orthogonal chemoproteomic methods can provide unbiased, comprehensive insights into the on- and off-target profiles of covalent inhibitors. Our study specifically highlights the limitations of traditional enrichment proteomics in distinguishing high-occupancy binders from low-occupancy binders, and it proposes a solution through a complementary scavenging proteomics approach that analyzes de-enriched fractions, providing target engagement ratios across the proteome. This framework facilitated the development of CNP7, a cyanopyrrolidine that covalently modifies HMGCS1's catalytic cysteine with remarkable selectivity, as assessed by comprehensive chemoproteomics. A 2.29 Å cryo-EM structure reveals how CNP7 engages the catalytic cysteine within HMGCS1's hydrophobic pocket. CNP7 treatment decreases HMG-CoA levels and induces global protein deprenylation within 4 h. Notably, CNP7 exhibits cell line-specific anticancer activity patterns that differ from those of statins, suggesting possible pathway node-specific vulnerabilities. Together, our study offers valuable chemical tools to modulate HMGCS1 activity and presents a framework for the rigorous characterization of covalent inhibitors in chemical biology and drug development.
History
DepositionNov 19, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2026Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hydroxymethylglutaryl-CoA synthase, cytoplasmic
B: Hydroxymethylglutaryl-CoA synthase, cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,3594
Polymers106,5822
Non-polymers7772
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Hydroxymethylglutaryl-CoA synthase, cytoplasmic / HMG-CoA synthase / 3-hydroxy-3-methylglutaryl coenzyme A synthase


Mass: 53290.832 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HMGCS1, HMGCS / Production host: Escherichia coli (E. coli)
References: UniProt: Q01581, hydroxymethylglutaryl-CoA synthase
#2: Chemical ChemComp-A1C1C / (3S)-1-[(Z)-iminomethyl]-N-({(1P)-3'-[(prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-3-yl}methyl)pyrrolidine-3-carboxamide


Mass: 388.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N4O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1700 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 589925 / Symmetry type: POINT

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